T cells are made in the thymus, a small organ situated under the breastbone near the heart, whose primary function is T-cell production. However, T cells ultimately come from hematopoietic (blood-producing) stem cells in the bone marrow, from which all blood-cell types begin. A progenitor cell leaves the bone marrow to seed the thymus, eventually giving rise to T cells. In the absence of instructions by the Notch protein, T-cell development does not occur, even in the presence of a normal thymus.

In this study-published in the most recent issue of Nature Immunology-the investigators found that Notch, a protein that regulates diverse cell-fate decisions in multi-cellular organisms, is active in very early T-cell progenitors in the thymus of mice. Notch contributes to the subsequent differentiation of these early T-cell progenitors into T cells.

"Notch signaling instructs multi-potent progenitor cell types to enter the T-cell developmental pathway," says senior author Avinash Bhandoola, MD, PhD, Assistant Professor of Pathology and Laboratory Medicine. "However, we don't yet understand in which tissue these instructions are being delivered, and which cell type is the recipient."

Co-author Warren Pear, MD, PhD, Associate Professor of Pathology and Lab Medicine and member of Penn's Abramson Family Cancer Research Institute and Institute for Medicine and Engineering, was one of the original discoverers of the role of Notch in T-cell development. His lab developed tools to block Notch signaling, which were key to identifying its function in T-cell progenitors. Findings from this current study suggest that Notch acts very early after progenitor cells enter the thymus, among other probable points in T-cell development.

Notch activates gene transcription in the nucleus of cells, and depending on the biochemical context, it turns certain pathways on, and others off. "To the extent that we know where, and in which cells Notch is acting, we may be able to figure out how Notch works in the thymus," says co-lead author Arivazhagan Sambandam, PhD, Research Associate, also in the Department of Pathology and Laboratory Medicine.

"Studying events in the thymus is important because intrathymic events may be a bottleneck in T-cell reconstitution, which is deficient in post-transplant patients," says co-lead author Ivan Maillard, MD, PhD, Research Associate in the Division of Hematology-Oncology and the Abramson Family Cancer Research Institute. "What the study allows us to do is begin to define exactly where intrathymic Notch signaling happens and where to look for problems and for the relevant molecular interactions."

In many clinical situations, early T-cell progenitors are likely to be deficient-especially in patients undergoing bone marrow or hematopoietic stem cell transplantation, in whom new T cells fail to be produced for long periods of time. In some, especially elderly patients, there is never true recovery of T cells, and such non-recovery is associated with problems such as infections. To improve the outcome of transplant patients, the process of T-cell development needs to be better understood. This may also be important in cancer patients who get profound immunosuppression from treatments and in AIDS patients when T cells are not made at a sufficient rate to replenish the T-cell pool.

The Pear and Bhandoola labs plan to apply the knowledge gained in their basic scientific studies to the clinic. According to Maillard, "In humans, it's more difficult to look inside the thymus, but we plan to use our unique Notch reagents in model systems to generate hypotheses about the exact nature of Notch control of T-cell development, eventually moving that knowledge to relevant clinical situations."

med.upenn/